Intraperitoneal Chemotherapy for Patients with Optimal Stage III Ovarian Cancer
ABSTRACT & COMMENTARY
Synopsis: Patients with optimal stage III epithelial ovarian cancer who received IP cisplatin/IV cyclophosphamide had a significantly longer survival time than those who received IV cisplatin/IV cyclophosphamide.
Source: Alberts DS, et al. N Engl J Med 1996;335:1950-1955.
In a recent phase iii study consisting of patients from the Southwest Oncology Group, the Gynecologic Oncology Group, and the Eastern Collaborative Oncology Group, Alberts et al randomized patients with optimal (£ 2 cm residual disease) stage III epithelial ovarian cancer postoperatively to receive either the combination of IP cisplatin and IV cyclophosphamide or the combination of IV cisplatin and IV cyclophosphamide for a total of six cycles. All patients had at least a bilateral oophorectomy, abdominal hysterectomy, omentectomy, and resection of all tumor masses to £ 2 cm residual disease no more than four weeks prior to starting chemo therapy. Prior to randomization, patients were stratified for residual disease (£ 0.5 cm vs > 0.5-2.0 cm), performance status, and cooperative group. Between 1986 and 1992, 654 patients were randomized, of them 546 were eligible; 390 patients had £ 0.5 cm residual disease. The pathological complete response rate as determined at second-look surgery was 36% in the IV arm and 47% in the IP arm. Patient survival on the IP arm (median, 49 months) was significantly longer than on the IV arm (median, 41 months). There were two treatment-related deaths on the IP arm and none on the IV arm. Clinical hearing loss and neuromuscular toxic effects were significantly more frequent and more severe in the IV-treated patients.
The authors conclude that, using the combination of cisplatin and cyclophosphamide, the IP administration of cisplatin is associated with superior patient survival time and less clinical hearing loss and neurotoxicity in patients with optimal stage III ovarian cancer.
COMMENT BY DAVID M. GERSHENSON, MD
Intraperitoneal chemotherapy has been used in the treatment of ovarian cancer since the 1950s, mainly for the palliation of malignant effusions. It gradually lost popularity as newer, more effective systemic chemo therapeutic agents were discovered, until the late 1970s, when a resurgence of interest in this strategy occurred. This resurgence was accompanied by a recognition of the pharmacological advantage of this route of administration and technical advances in this area (i.e., the invention of implantable devices such as the Tenckhoff catheter or the Port-a-Cath for intraperitoneal drug delivery). Over the past 15 years or so, scores of phase I and II studies using intraperitoneal chemotherapy in patients with ovarian cancer have been conducted. Many of these studies reported responses, and even prolonged survival, in patients with refractory ovarian cancer, but there was no comparison with the IV route of administration. It did appear that, if IP therapy had any role, it was for patients with minimal residual disease. Obviously, the IV route is less expensive and is associated with fewer drug delivery complications than the IP route. Therefore, an improvement in either quality of life (less toxicity) or survival was necessary to prove the value of IP chemotherapy.
Such was lacking until this recent report. In fact, there was such disappointment in this technique, even by early proponents, that it was almost put on the shelf permanently. But the findings of this study have snatched IP chemotherapy from the jaws of onco-hell. In fact, the results have been widely disseminated in the lay press, and many of my patients have inquired about the advantages of such treatment. As is characteristic of such publicity, the perception of many patients and their families is that such treatment represents a major breakthrough in our fight against this devastating disease. Despite the findings, however, I remain skeptical about the advantages of IP therapy. Confirmatory trials are necessary before such treatment is embraced by the medical community. We have had several other instances of fanfare from findings of one trial, only to find that mature data from further studies reveal discordant results. It was only a few years ago that several experts in the field believed strongly that doubling the dose of platinum-based chemotherapy improved survival. We now know, based on several reports, that doubling the dose of platinum does not appear to provide a survival advantage. In the meantime, each of us must give his or her patients the best advice possible about treatment options.
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